The candidate has recently joined the staff at the Massachusetts General Hospital (MGH) and received an appointment at Harvard Medical School effective July 2012. Over the last four years the candidate has studied the epidemiology and genetics of atrial fibrillation (AF), achieved a Master of Public Health degree, completed cardiac electrophysiology training, and established scientifically productive relationships with hi mentors. This Career Development Award is motivated by the public health importance of AF, which affects over 3 million Americans and is increasing in incidence and prevalence worldwide. Substantial morbidity and mortality are attributable to AF, including increased risks of disabling stroke, heart failure, and death. Furthermore, AF is responsible for an estimated $26 billion in annual health care costs in the United States. A widespread heritable component underlying AF is now recognized, and common genetic variants associated with AF have been discovered. Despite advances in the understanding of AF genetics, knowledge gaps remain. Associated signals at discovered AF susceptibility loci span up to hundreds of thousands of base pairs and remain poorly characterized. Data suggest that independent susceptibility signals may exist at known loci, and may both facilitate the identification of individuals at risk for AF as well as localize functional elements involved in AF pathogenesis. Relations between AF susceptibility variants and morbidity from AF remain unexplored. Associations between AF associated variants and clinical manifestations of AF may enable efforts to apply genetic and other discoveries to patient management in an effort to prevent morbidity. The candidate seeks to address these knowledge gaps by leveraging the power and complementarity of well-phenotyped cohorts spanning hospital-referral, community-based, and clinical trials samples. Specifically, the candidate proposes to: 1) discover independent AF genetic susceptibility variants in the international CHARGE consortium; 2) determine the clinical and genetic predictors of AF progression in cohorts from MGH and the Framingham Heart Study; and 3) examine relations between AF susceptibility variants and stroke in individuals with and without AF in two Thrombolysis In Myocardial Infarction Study Group trials. This K23 is designed to foster independence through advanced training in genetic epidemiology, biostatistics, and clinical trial methods. The application draws upon strengths of different cohorts and experienced mentors in a multidisciplinary fashion. The aims will inform our understanding of the mechanisms, clinical features, and outcomes of AF, a morbid arrhythmia of substantial public health importance. In future R01 applications the candidate will be poised to test whether application of genetic knowledge can facilitate prevention of AF related morbidity, and whether genetic variants associate differentially with response to pharmacologic agents used to treat patients with AF.